FDA Approval of Generic IMITREX STATdose Sheds Some Light on Auto-Injector “Sameness” Issues – But What About Other Combination Products?

FDA’s recent approval of ANDA No. 090358 for an AB-rated generic version of IMITREX STATdose (sumatriptan succinate) Injection, approved under NDA No. 020080, puts some meat on the bones of the Agency’s July 2009 consolidated response to two citizen petitions (here and here) submitted by King Pharmaceuticals, Inc. (“King”) requesting that FDA decline to approve (or stay the approval of) ANDAs that reference a drug product containing an auto-injector device component – and in particular ANDAs for a generic version of IMITREX – unless the auto-injector component is “identical” to that of the Reference Listed Drug (“RLD”) in terms of performance, physical characteristics, and labeled instructions. As we previously reported, FDA granted in part and denied in part the King petitions.

FDA’s consolidated petitions response, which is specific to combination products with an auto-injector component, provides some general guidance and insight into the Agency’s thinking on what “sameness” means with respect to auto-injector performance, physical characteristics, and labeling instructions. For example, FDA commented that “when reviewing an ANDA for a combination product that includes an auto-injector constituent part, [the Agency] must evaluate the auto-injector constituent part of the combination product for which ANDA approval is sought to ensure that its performance characteristics and critical design attributes will result in a product that will perform the same as the RLD.” FDA clarified, however, that “[t]his does not mean . . . that all design features of the auto-injector in the ANDA and its RLD must be exactly the same. Some design differences may be acceptable as long as they do not significantly alter product performance or operating principles and do not result in impermissible differences in labeling.”

FDA also commented that “[f]or an ANDA for a product intended for emergency use by patients without professional supervision (such as a prefilled auto-injector indicated for emergency treatment of allergic reactions), it is particularly important to ensure that patients in an emergency situation can use the product safely and effectively in accordance with instructions provided for the RLD without additional physician intervention or retraining prior to use,” and that “[a] similar standard may be applied to certain products not intended for emergency use, if appropriate.” Indeed, in the case of sumatriptan auto-injectors, FDA noted that “individuals experiencing migraines . . . may experience varying degrees of mental impairment, and this may affect the usability of an auto-injector, leading to possible errors or misadministration of the product,” and as such, “in reviewing an ANDA referencing [IMITREX], FDA will have to consider whether, given the characteristics of the proposed auto-injector constituent, the product can be safely substituted for the RLD without additional physician intervention or retraining prior to use.”

With respect to labeling and therapeutic equivalence issues, King had requested that “FDA require ANDA sponsors of drug products containing auto-injectors to use the same physical description of an auto-injector, the same operating instructions, and the same illustrations contained in the RLD labeling,” and that “the same standard should apply in assessing therapeutic equivalence. . . .” FDA responded that although the auto-injector component in an ANDA for a combination product should be equivalent to that of the RLD product in terms of performance, operating principles, and critical design attributes. “labeling need not be identical.” According to FDA:

Certain minor labeling changes may be acceptable to identify certain permissible differences between the ANDA and its RLD (e.g., to identify a change in materials to make the product lighter or to make it more robust or durable), as are minor differences (such as cosmetic appearance, color, shape) between the RLD and ANDA labeling when they do not interfere with operating conditions. For products that require physician training before unsupervised patient use, differences in operation that require retraining prior to use are not expected to be acceptable in an ANDA. FDA will consider other proposed differences in labeling on a case-by-case basis.

That brings us to FDA’s decision to approve an ANDA for an AB-rated version of IMITREX STATdose. A comparison of the FDA-approved labeling for IMITREX STATdose and its AB-rated generic version approved under ANDA No. 090358 posted on DailyMed – see here and here – while largely identical (as required by the FDC Act), includes different operating instructions under the “Patient Information – How To Use” sections of each set of labeling. Consistent with FDA’s consolidated petitions response, however, the Agency apparently determined that these differences “do not interfere with operating conditions” and that the differences in operation do not require physician retraining.

Whether FDA will apply the seemingly flexible approach the Agency apparently took in approving a generic version of IMITREX STATdose to other combination products that do not contain an auto-injector – such as Metered Dose Inhaler (“MDI”) and Dry Powder Inhaler (“DPI”) drug products – remains to be seen.

Still awaiting a substantive response from FDA is a December 2009 citizen petition (Docket No. FDA-2009-P-0597) requesting “that specific legal and scientific requirements be upheld in the review of proposed generic copies of [MDI and DPI] products containing fluticasone propionate and/or salmeterol xinafoate” (i.e., SEREVENT DISKUS, FLOVENT DISKUS, FLOVENT HFA, ADVAIR DISKUS, and ADVAIR HFA). For example, the petition requests that FDA not approve any ANDA referencing certain inhalation products unless the proposed generic version “conforms to the [RLD] in its patient instructions for use and handling. . . .” “Different instructions for how to use an inhaler properly – including priming, dosing, cleaning, and storing – are simply too significant to possibly fit into the very limited zone of labeling differences that the law permits for generic drugs,” according to the petitioners. Thus, the ultimate question for FDA seems to be this: To what extent must a proposed generic product be interchangeable in patient hands? Wrapped up in this question are questions about similar external design (shape and size), number of doses, dose counter placement, and color scheme.